PROJECT SUMMARY This is an application for continued support for years 41-45 of a postdoctoral training program in medical genetics based in the Department of Molecular and Human Genetics (DMHG) at Baylor College of Medicine (BCM). The DMHG is a bridging department with major clinical activities and strong programs in basic, translational, and clinical research. It uniquely integrates many of the activities that are traditionally found dispersed through many academic departments and centers at most US academic institutions into a single department at BCM. The emphasis of this postdoctoral program is on medical and human genetics and on molecular approaches. There are 90 training faculty, 69 with primary and 21 with secondary appointments in the DMHG (up from 79 in the last renewal submission in 2012). As part of a transition plan in program leadership in 2012, Dr. Lee, took over as the PI of this training grant in renewing it for the current funding cycle (years 36-40) from Dr. Arthur L. Beaudet. In continuation of this transition, Dr. Lee was appointed Chairman of DMHG in Dec 2014 after an international search. An ambitious strategic plan has been implemented over the past two years that has further enhanced the training environment including new faculty recruitment, development of new clinical training tracks, formation of a diagnostic laboratory joint venture, and development of a virtual platform to facilitate patient engagement in clinical care, education, and research. However, the core of the Department mission remains research spanning all areas of human and model organism genetics. Trainees derive mainly from ACGME and ABMGG approved residency and fellowship programs. The primary focus of the program is to attract highly qualified MD and MD/PhD trainees who seek an intensive and substantial research experience. In the past four years of funding, 87.5% of slots were assigned to MD or MD/PhD trainees. Powerful drivers of training include faculty integration at the Department, Center, and NIH program levels and leading clinical implementation of innovative technologies including array comparative genomic hybridization, whole exome sequencing, metabolomics, and cell free noninvasive prenatal gene sequencing in this application. Our stellar alumni who now populate our and many other medical genetics programs support the success of this central tenet. Major strengths of the training environment include a large clinical genetics component; large, comprehensive, and sophisticated diagnostic laboratories; 170,000 square feet of space for the department activities; strong institutional commitment; a genetic graduate student program with relevant course work; ACGME and ABMGG-certified training programs; high national ranking of NIH funding for genetics departments (1st); NIH Large Scale Sequencing Center; NIH Intellectual and Developmental Disability Research Center; NIH Center for Mendelian Genomics; NIH Undiagnosed Diseases Network (UDN) Clinical Site (CS), Sequencing Core (SC), and Model Organism Screening Center (MOSC); and NIH Knockout Mouse Phenotyping Program (KOMP3).